Treatment (Curative intention with high dose chemotherapy) 9
The general approach to current therapy has not changed substantially in recent years. The initial assessment evaluates whether a patient is considered a candidate for intensive induction chemotherapy. Although an assessment of the risk of treatment-related mortality (TRM) after intensive therapy is usually most relevant in older patients (commonly above the age of 65 years), age is merely one, and not the most important, predictor of TRM. Therefore, age alone should not be the decisive determinant in guiding therapy. 6
Results from cytogenetics should be obtained preferably within 5 to 7 days. Results from NPM1 and FLT3 mutational screening should be available within 48 to 72 hours (at least in patients who are eligible for intensive chemotherapy), and the results from additional molecular genetic testing should be available within the first treatment cycle. 6
Eligible patients first undergo induction chemotherapy to achieve complete remission (CR). Unfortunately, minimal residual disease often persists in CR, and relapse will inevitably occur if treatment is discontinued. Therefore, a favorable response to induction therapy should be followed by consolidation therapy in order to eradicate any residual disease and achieve lasting remission.1
Induction therapy consists of 3 days of an anthracycline and 7 days of cytarabine. Complete remission rates are achieved of 60% to 80% in younger adults and 40% to 60% in those aged ≥ 60 years. 6
Role of other drugs: FLT3 inhibitors. The RATIFY trial evaluated intensive induction and consolidation chemotherapy plus midostaurin or placebo followed by a 1-year midostaurin/placebo maintenance phase in 717 patients aged 18 to 60 years with FLT3-mutated AML.Use of midostaurin increased the CR rate when all CRs reported within 30 days of ending protocol therapy were considered (68% vs 59%; P 5 .04). The trial met its primary end point in improving OS (hazard ratio 0.78; P=.009), regardless of whether patients received allogeneic HCT. Thus, patients with FLT3-mutated AML may be considered to receive intensive chemotherapy in combination with midostaurin.6
Midostaurin is indicated and administered in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation chemotherapy, and for patients in complete response followed by Rydapt single agent maintenance therapy up to 12 months, for adult patients with newly diagnosed acute myeloid leukaemia (AML) who are FLT3 mutation-positive. 8
Patients in remission should be offered consolidation therapy to eradicate residual disease and prevent relapse. Available options for consolidation include chemotherapy and allogeneic hematopoietic stem cell transplant (allo-HSCT). When choosing between these different options, the risk of TRM should be weighted against the risk of treatment failure or relapse. 1
Consolidation regimens include single-agent cytarabine at high doses and multiagent chemotherapy which lead to similar outcomes. 6
Open questions remain regarding the optimal number of cycles of consolidation therapy. In most studies 2-4 cycles have been given after attainment of CR.6
AML is the most frequent indication for allogeneic HCT, with a 10% annual increase in transplants performed worldwide. Expanded use of mismatched and unrelated donors and cord blood means that a donor can be found for most patients. Further, nonmyeloablative or reduced-intensity conditioning (RIC) regimens allow allogeneic HCT for patients aged up to 75 years. Nonetheless, in reality, only a minority of AML patients undergo transplantation due to older age, comorbidities, toxicity of prior therapy, inability to achieve remission, and early relapse or refractory leukemia. 6
Patients unfit for intensive chemotherapy
Some AML patients will not tolerate intensive chemotherapy. Several risk scoring systems are available that use patient-specific and disease specific factors to make the choice of intensive or alternative treatment. 6
Treatment alternatives for unfit patients are limited to best supportive care, low-intensity treatment, or clinical trials with investigational drugs. 6
1. De Kouchkovsky I, Abdul-Hay M. Blood Cancer J. 2016 Jul;6(7):e441.
2. American Cancer Society. Acute myeloid leukemia [Internet]. [cited 2019 Feb 21] Available from: https://www.cancer.gov/types/leukemia/hp/adult-aml-treatment-pdq.
3. Surveillance Epidemiology and End Results (SEER). SEER stat fact sheets: acute myeloid leukemia [Internet]. [cited 2019 Feb 21] Available from: http://seer.cancer.gov/statfacts/html/amyl.html.
4. G Juliusson, J Abrahamsson, V Lazarevic, et al., for the Swedish AML Group and the Swedish Childhood Leukemia Group. Leukemia. 2017 Mar; 31(3): 728–731.
5. Lin et al. Clin Med Insights Oncol. 2012; 6:205-217
6. Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Blood. 2017 Jan;129(4):424-47.
7. National Cancer Institute. Adult acute myeloid leukemia treatment (PDQ®)-Patient Version. http://www.cancer.gov/types/leukemia/patient/adult-aml-treatment-pdq
8. Rydapt (midostaurin) Summary of Prodcut Characteristics
9. Swedish AML gudlines WWW.sfhem.se/riktlinjer